Much of a cell's DNA is transcriptionally silent because it is packaged in an inaccessible chromatin architecture. Chromatin remodeling enzymes play critical roles in preparing appropriate genes for transcription in the correct cell type by covalently modifying the flexible tails of histones that stick out of the nucleosomes and contact DNA. Altering chromatin architecture has major medical implications. Some cancers are at least in part due to epigenetic silencing of a tumor suppressor gene whose DNA sequence remains wild type. Likewise, several debilitating inherited diseases are caused by problems in imprinted genes where a wild type allele is present but silent. Finally, a major obstacle to successful gene therapy is the fact the even if exogenous DNA enters a cell, it often has no therapeutic effect because the gene is packaged in silent chromatin. The Drosophila MSL (male-specific lethal) dosage compensation complex provides an outstanding model system to study chromatin modifications because, 1) it acts on more than a thousand unrelated genes on the X chromosome, but not the autosomes, 2) its major MSL protein and roX RNA components have been identified, 3) the change in gene expression is very subtle, only two-fold, 4) the MSL complex is only required in males, allowing in vivo analysis of inactive partial/mutant complexes in females, and 5) the superb cytology of polytene chromosomes provides unequaled material to study target recognition in vivo. The MSL proteins and roX RNAs will be functionally dissected by characterizing mutants in vivo. The MSL complex is held as a model of epigenetic regulation because of its spectacular spreading behavior that can be directly visualized on polytene chromosomes. A new model to explain how cis spreading operates will be tested. New search methods will be developed to identify currently unknown noncoding RNAs. [unreadable] [unreadable]